In this project we focused our studies on the genetic basis both of orthopoxvirus virulence and of host resistance to virus infection. The acquired knowledge should contribute towards the development of safe, effective, recombinant vaccinia virus vaccines for animal and human use. A deletion mutant of cowpox virus has been constructed which lacks a functional gene for a 38 kilodalton protein involved in the generation of a hemorrhagic pock on the chlorioallantoic membrane of the chicken embryo. The mutant pock contains significantly more heterophils than the WT, and the significance of this observation is being investigated. An activity from vaccinia virus infected culture supernatants has been identified that causes 3H-thymidine incorporation into DNA of cells from human peripheral blood lymphocyte populations. Experiments are ongoing to determine whether the activity is virus-coded and the mechanism of action on the target cell(s). Using the cross- intercross system, the A strain of mouse (disease susceptible) was crossed with a disease resistant C57BL/6J mouse in order to generate a mouse strain A.B6-Rmp (resistance to mousepox) congenic for the resistance loci. This will aid in studying the non-H2 innate resistance genes important in resistance to disease.